Synthesis of mixed phosphorotrithioates from white phosphorus

Article abstract of DOI:10.1039/d0gc02985h

The first general and high-yielding synthesis of mixed phosphorotrithioates (R1S)2P(O)SR2 involving white phosphorus, disulfides, and alkyl halides is presented, which provides the shortest and environmentally benign method to synthesize these compounds of practical importance. Only one method for the formation of (R1S)2P(O)SR2 from elemental phosphorus has been developed. Here, with the use of KOH as a base and DMSO-toluene as a solvent, various disulfides couple readily with white phosphorus to give O-potassium S,S-dialkylphosphorotrithioates (R1S)2P(S)OK in almost quantitative yields, which react with alkyl halides to form (R1S)2P(O)SR2 in high yields. The reaction is characterized by the complete conversion of white phosphorus. Moreover, this method can be easily adapted to large-scale preparation. Our mechanistic data suggest that the attack of RSK on S,S,S-trialkyl phosphorotrithioates and subsequent C-S bond cleavage, the Michaelis-Arbuzov-like dealkylation, are the key steps in the formation of (R1S)2P(S)OK.

Full text of DOI:10.1039/d0gc02985h

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DOI: 10.1039/D0GC02985H
ARTICLE
Synthesis of mixed phosphorotrithioates from white phosphorus
Xinlei Huangfu, Yue Zhang, Peiyun Chen, Guozhang Lu, Yinwei Cao, Guo Tang,* and Yufen Zhao
Received 00th January 20xx,
Accepted 00th January 20xx
The first general and high-yielding synthesis of mixed phosphorotrithioates (R1S)2P(O)SR2 involving white
phosphorus, disulfides, and alkyl halides is presented, which opens the shortest and environmentally benign
way to these compounds of practical importance. Only one method for the formation of (R1S)2P(O)SR2 from
elemental phosphorus has been developed. Here, with the use of KOH as a base, DMSO-toluene as a solvent,
various disulfides couple readily with white phosphorus to give O-potassium S,S-dialkylphosphorotrithioates
(R1S)2P(S)OK in almost quantitative yield, which react with alkyl halides to form (R1S)2P(O)SR2 in high
yields. The reaction is characterized by a complete conversion of white phosphorus. Moreover, this method
can be easily adapted to large-scale preparation. Our mechanistic data suggest that the attack of RSK on S,S,S-
trialkyl phosphorotrithioates and subsequent C−S bond cleavage, the Michaelis-Arbuzov-like dealkylation,
are the key steps in the formation of (R1S)2P(S)OK.
DOI: 10.1039/x0xx00000x
In the past 70 years, only six methods for the preparation of
C−S−P bonds from P4 have been developed.32-41 In 1951, Stevens
Introduction
The importance of sulfur-containing organophosphorus molecules as
pharmaceuticals, agrochemicals, and functional materials has fuelled
an ever-increasing interest in developing efficient and sustainable
C−S−P bond forming reactions in phosphorus chemistry.1-5 In fact,
more than 60 molecules containing at least one C−S−P bond
are widely used as agricultural pesticides (Fig 1).5 A wide array of
treated P4 with disulfides at very high temperatures to produce the
corresponding trithiophosphites [P(SR)3].32 Wu later demonstrated
that this process could be conducted in dipolar aprotic solvents under
much milder conditions in the presence of KOH.33 In 1978, Hudson
et al. investigated the sulfenylation of P4 with sodium alkanethiolates
in CCl4 under
a
nitrogen atmosphere to produce
trithiophosphites.34,35 In 2005, Sinyashin and coworkers successfully
prepared P(O)(SPh)3 from thiophenol and P4 in refluxing acetonitrile
under air conditions.36-38 In 2019, we discovered an efficient
photochemical process for accessing phosphorotrithioates from
arythiols and P4 using visible light and Eosin Y as a photosensitizer.
Addition of hydrogen peroxide can oxidize the trithiophosphites to
the target phosphorotrithioates.39 In 2020, we developed the first
general synthesis of P(SR)3 and P(O)(SR)3 from P4 and thiols. Both
arythiols and alkylthiols are tolerant in this transformation.40 These
breakthroughs laid the foundation of the systematic use of white
phosphorus for the synthesis of unavailable or unknown
phosphorotrithioates which contain the same three RS groups.
phosphorothioate,
phosphonothioate
and
phosphinothioate
compounds may be readily prepared from R2P(O)H compounds and
their derivatives.6-11 However, multistep and environmentally toxic
processes are usually involved to make R2P(O)H compounds from
white phosphorus (P4) via a chlorinated process followed by a
nucleophilic substitution reaction.12 Although the activation of P4 by
main group elements,13-18 transition-metal complexes19-24 and rare-
earth-metals25-28 started and is still being developed well, the
synthesis of organophosphorus compounds (OPCs) from white
phosphorus is still the main challenge in this area.29-31
O
P
S
O
P
S
O
P
EtO
S
C3H7-n
EtO
S C4H9-sec
SC4H9-n
n-C4H9S
C3H7-n
C4H9-sec
Compared to P(O)(SR)3, (R1S)2P(O)OR2 and (R1O)2P(O)SR2 as
SC4H9-n
Ethoprophos
Sebufos
general structures in pesticide chemicals,5
(R1S)2P(O)SR2 is
Tribufos
regarded as difficult structures to access, and only very limited
methods have been developed thus far.42-44 We speculated that
replacing one OR group with SR group in these pesticide chemicals,
would provide an opportunity to adjust their bioactivities. In 1977,
Stec and coworkers described the synthesis of R1SP(O)(NHPh)2,
(R1S) (R2S)P(O)NHPh, and (R1S) (R2S)P(O)SR3 from P(O)(NHPh)3,
carbon disulfide and alkyl halides (Scheme 1A).42 In 2009, Trofimov
O
O
O
P
O
EtO
P
S
S
Ph
EtO
P
S
MeO
S
Ph
Ph
OEt
Kitazin
O
OMe
Endothion
O
Edifenphos
Figure 1. Selected agrochemicals.
and
colleagues
synthesized
O-potassium
S,S-dialkyl
Department of Chemistry, College of Chemistry and Chemical Engineering, and
the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University,
Xiamen, Fujian 361005, China. E-mail: t12g21@xmu.edu.cn
Electronic Supplementary Information (ESI) available: Experimental procedures for
the synthesis, spectral data and NMR spectra of compounds 4-40. See
DOI: 10.1039/x0xx00000x
trithiophosphates in 12–20% yields through the reaction of red
phosphorus with alkanethiolate anions.43,44 O-Potassium S,S-dialkyl
trithiophosphates are readily alkylated with organic halides to form
mixed S,S,S-trialkyl trithiophosphates [(R1S)2P(O)SR2, Scheme
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ARTICLE
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1B].43,44 Inspired by the above results and our study on the However, the yield of 3 decreased when the temperature was
View Article Online
construction C−S−P bond,45-47 we envisioned that the base-promoted increased to 100 °C or decreased to 60 °C (entries 11 and 13). When
DOI: 10.1039/D0GC02985H
S-P coupling of (RS)2 and P4 might generate P(SR)5 or (RS)4P+SR- the loading of KOH or (n-C4H9S)2 (2) was decreased, the yield of 3
species, which would undergo further dealkylated Michaelis- also decreased (entries 14 -16). The reactions of red phosphorus with
Arbuzov reaction, eventually leading to O-potassium S,S-dialkyl (n-C4H9S)2 under standard conditions gave a 32% conversion of red
trithiophosphates [(RS)2P(S)OK, Scheme 1C]. Herein, we report the phosphorus, and produced [(n-C4H9S)2P(S)OK] (3) with a yield of
successful high-yielding synthesis of (R1S)2P(O)SR2 from (RS)2, P4 25% based on the starting red phosphorus (a yield of 78% based on
and alkyl halides through a base-promoted RS–P coupling followed the converted red phosphorus, entry 17).
by Michaelis-Arbuzov reaction and alkylation.
Table 1. Synthesis of (n-C4H9S)2P(S)OK (3)a
A) Stec:
O
P
S
P
NaH
CS2
3 PhNH2
P
PhNH
NHPh
S
P
PhNH
OK
POCl3
base, solvent
Ar, T (oC), 4 h
+
(n-BuS)2
P
PhNH
1/4
SBu-n
K
PhNH
R1X
SR1
n-BuS
P
P
O
2
1
(P4)
6.2 mg
O
n eq.
3
NaH
CS2
O
NaH
CS2
R3X
R2S
P
SR1
PhNH
P
R3S
R2X
PhNH
Entry
1
n
Base(mol%)b Solvent (1 mL)
T(oC)
25
Yieldc
3.0 KOH (200)
3.0 KOH (200)
3.0 KOH (200)
3.0 KOH (200)
3.0 KOH (200)
3.0 KOH (200)
3.0 KOH (200)
3.0 KOH (200)
3.0 Based
DMSO
11%
22%
0%
B) Trofimov:
S
2
DMF
25
25
25
25
25
25
25
25
25
60
80
100
80
80
80
80
R1SH, KOH, DMSO
method A: 125 oC, 4 h
method B: MW, 5 min
O
P
R2X
R1S
P
OK
R1S
< 20%
R1S
SR2
Pred
3
PhMe
R1S
4
PhMe+CH3CN
PhMe+ THF
PhMe+1,4-dioxane
PhMe+DMF
PhMe+DMSO
PhMe+DMSO
PhMe+DMSO
PhMe+DMSO
PhMe+DMSO
PhMe+DMSO
PhMe+DMSO
PhMe+DMSO
PhMe+DMSO
PhMe+DMSO
0%
yield:
5
0%
C) This work:
S
P
6
0%
O
P
R1S-SR1
+
0.25 P4
R2X
OK
R1S
KOH
R1S
SR2
7
56%
81%
<5%
20%
86%
>95%
92%
80%
38%
84%
25%
R1S
toluene, DMSO
Ar
R1S
8
9
3 P-S bonds + 1 S-C bond
almost quantitative yield
mixed trithiophosphates
easy operation
10e
11
12
13
14
15
16
17f
3.0 KOH (200)
3.0 KOH (200)
3.0 KOH (200)
3.0 KOH (200)
3.0 KOH (150)
2.0 KOH (200)
2.5 KOH (200)
3.0 KOH (200)
Scheme 1. Synthesis of (R1S)2P(O)SR2.
Results and discussion
A preliminary optimization of the reaction conditions was carried
out with P4 (1) and (n-C4H9S)2 (2) as reaction partners (Table 1).
Inspired by our previous work, KOH was investigated in this
reaction.40 In the presence of KOH, DMSO, DMF and toluene
afforded product O-potassium S,S-dibutylphosphorotrithioate [(n-
C4H9S)2P(S)OK] (3, 31P NMR: s, 75 ppm) with very low yield under
argon at 25 °C for 12 h (entries 1-3). Other mixed solvents such as
toluene-CH3CN, -THF, -1,4-dioxane were also ineffective (entries 4-
6). Pleasingly, the targeted salt 3 was detected in 56% yield in the
mixed solvent of toluene (0.5 mL) and DMF (0.5 mL) at room
temperature for 12 h (entry 7). Furthermore, an 81% yield was
achieved with the mixed solvent of toluene and DMSO application
(entry 8). Other alkali-metal salts (K2CO3, Na2CO3) and organic
bases (DBU and NEt3) could not promote this process (entry 9). The
reaction was carried out in air, in an open flask with a calcium
chloride drying tube, leading to salt 3 and (n-C4H9S)3P(O) in 20%
and 60% yields, respectively (entry 10). The reaction performed well
at 80 °C for 4 h and gave salt 3 in almost quantitative yield (entry
12). The structure of 3 was confirmed by its 1H and 13C NMR
spectra and mass spectrometry (see ESI). Indeed, no P4 left within 30
min determined by 31 P NMR analysis of the crude reaction mixture.
To ensure 100% conversion of white phosphorus, the reaction time
was prolonged to 4 h. Trofimov synthesized salt 3 in 12% yield
through the reaction of red phosphorus with 1-butanethiol.43 In our
method, using (C6H5)3P(O) (26 ppm) as an internal standard, a single
pulse 31P NMR experiment showed over 95% conversion to salt 3.
a Reaction conditions: (n-C4H9S)2 (n equivalents of disulfide per P-atom), P4
(6.2 mg, a 0.10 M solution of P4 in toluene, 0.5 mL), and base in solvent (1
mL) were stirred for 4 h in Ar. Mixed solvents: toluene (0.5 mL) + other
solvent (0.5 mL). mol% per P-atom. Yield of 3, determined by 31 P NMR
b
c
analysis of the crude reaction mixture using (C6H5)3P(O) as an internal
standard. d Base: K2CO3, Na2CO3, DBU or (Et)3N as a base. e Open to air.
f
Red phosphorus (6.2 mg) was used instead of P4.
P
P
O
P
BnX
(1.5 equiv)
(n-BuS)2
Sn-Bu
1/4
n-BuS
standard
conditions
P
P
S-Bn
4
conditions
1
(P4)
(table1, entry12)
6.2 mg
conditions
yield
BnX
BnCl
BnCl
BnCl
44%
87%
90%
rt, 12 h
KI(0.2 equiv), rt, 12 h
80 oC, 12 h
KI(0.2 equiv), 80 oC, 4 h
NaI(0.2 equiv), 80 oC, 4 h
rt, 12 h
BnCl
BnCl
BnBr
BnBr
95%
90%
95%
KI(0.2 equiv), rt, 4 h
95%
Scheme 2 Synthesis of (n-C4H9S)2P(O)SBn (4) in one-pot.
2 | J. Name., 2012, 00, 1-3
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Table 3. Scope of disulfides a
As
high-yielding
synthesis
of
O-potassium
S,S-
View Article Online
DOI: 10.1039/D0GC02985H
dibutylphosphorotrithioate (salt 3) involving white phosphorus and
disulfides was found, we investigated whether the synthesis of
mixed phosphorotrithioates could be carried out in one-pot directly
from white phosphorus without the isolation of intermediate 3
(Scheme 2). After stirring (n-C4H9S)2 (2) and P4 for 4 h at 80 °C in
argon, we added benzyl chloride, and then the mixture was stirred at
O
1) KOH, Tol. DMSO
Ar, 80 oC, 4 h
R1S
P
R1S
SR2
(R1S)2
0.25 P4
+
2) R2Cl, KI, T (oC), 4-12 h
product, yield
O
O
S
O
S
S
P
P
P
S
Ph
S
Ph
S
S
Ph
S
room temperature for another 12 h, giving product
(n-
S
C4H9S)2P(O)SBn (4) in 44% yield. When the reaction was heated at
80 °C, product 4 was obtained in 90% yield. The yield of 4 increased
obviously (87%, rt; 95%, 80 °C) with the use of KI as an additive.
The alkylation reaction was highly regiospecific, no O-alkylated
product was detectable in 31P NMR spectra of the crude reaction
mixture. Sodium iodide was also a good additive. Benzyl bromide
could react well with 3 to form product 4 in almost quantitative yield
at room temperature.
, 83%,T: 80 oC
(85%, T: rt)b
28
, 95%,T: 80 oC
, 90%,T: 80 oC
30
29
S
O
P
O
S
O
S
S
S
Ph
P
P
S
Ph
S
S
Ph
S
, 95%,T: 60 oC
(95%, T: rt)b
, 87%,T: 40 oC
(88%,T: rt)b
, 95%,T: 80 oC
32
33
31
O
O
O
S
P
Ph
S
Table 2. Scope of alkyl halides a
S
P
P
S
S
Ph
S
S
S
S
O
Ph
34
1) KOH, Tol. DMSO
SR1
Ar, 80 oC, 4 h
2) R1Cl, KI, 80 oC, 4-12 h
n-BuS
n-BuS
product, yield
P
, 88%b,c, T: rt
, 95% , T: 60 oC
d
, 85% , T: 60 oC
d
(n-BuS)2
0.25 P4
+
36
35
1
S
b
b
O
O
4
5
6
7
8
9
, R = H, 95%(95%)
, R = 2-Me, 93%
, R = 3-Me, 93%
, R = 4-Me, 92%
, R = 4-t-Bu, 93%
, R = 4-CH=CH2, 95%
10
, R = 4-CHO, 95%
, R = 4-CN, 86%
, R = 4-NO2, 94%
, R = 4-F, 92%
O
S
P
P
S
S
11
12
13
14
15
n-BuS
P
SBu-n
S
S
S
R
CH2
, 92% , T: 60 oC
d
, 81% , T: 60 oC
d
37
38
, R = 4-Cl, 93%
, R = 4-Br, 89%
O
O
O
O
P
n-BuS
P
S
n-BuS
P
S
n-BuS
P
Ph
S
S
, 80%
S
O
S
n-BuS
n-BuS
n-BuS
S
S
P
N
S
S
Ph
16
, 95%
17
18
, 90%
, 80% , T: 60 oC
d
, 80%c,e, T: 50 o
40
C
39
O
P
O
O
n-BuS
n-BuS
P
n-BuS
P
S
Ph
S
a
Reaction conditions: 1) Disulfide (0.6 mmol), P4–toluene solution (P4: 6.2
n-BuS
n-BuS
n-BuS
mg, a 0.10 M solution of P4 in toluene, 0.5 mL), DMSO (0.5 mL), KOH (0.4
mmol, 22.4 mg), with stirring under argon at 80 °C for 4 h; 2) RCl (1.5
equiv), KI (0.2 equiv) with stirring at 80 °C for 4-12 h; Yields of isolated
products. b BnBr (1.5 equiv), 4 h. c Water (20 μL) was added in step 1, rt, 8 h.
d n-C4H9Br (2.0 equiv), 12 h. e n-C4H9Br (3.0 equiv), 12 h.
d
c
21
c
, 93%
20
, 95%
19
, 90%
O
P
O
n-BuS
n-BuS
P
S
S
NHBoc
n-BuS
n-BuS
from n-C8H17Cl
d
d,e
22
, 95%
23
, 90%
Having the optimal conditions in hand, we next examined the
reactions of alkyl halides with (n-C4H9S)2 and P4 to probe the scope
of the reaction (Table 2). With alkyl and alkenyl substitution on
benzene, these compounds reacted efficiently to give the desired
products (4−9) in high yields, indicating that the position on the
benzene ring exerted a small influence. Some electron-withdrawing
CHO, CN and NO2 groups were investigated and gave the
corresponding products 10−12 in 86%−95% yields. Halogen atoms
such as fluoro, chloro, and bromo on the aromatic ring were not
affected under the present reaction conditions to afford the
corresponding products 13−15 in 89%−93% yields. It was found that
1-(chloromethyl)naphthalene, 2-(chloromethyl)pyridine and 3-
chloro-2-methylprop-1-ene reacted smoothly to give the
corresponding products 16−18 in 80%−95% yields. Indeed, the
substrates were not limited to the above-mentioned benzyl halide
derivatives; other alkyl halides bearing terminal alkyne bond, amide,
nitrile, acetal, keto and ester groups worked well in this process to
O
O
P
O
CN
n-BuS
P
S
n-BuS
n-BuS
S
O
n-BuS
d,e
d,f
24
, 76%
25
, 83%
O
O
P
O
O
n-BuS
P
S
n-BuS
n-BuS
S
O
n-BuS
c,e
c,e
26
, 86%
27
, 95%
a Reaction conditions: 1) (n-C4H9S)2 (0.6 mmol), P4–toluene solution (P4: 6.2
mg, a 0.10 M solution of P4 in toluene, 0.5 mL), DMSO (0.5 mL), KOH (0.4
mmol, 22.4 mg), with stirring under argon at 80 °C for 4 h; 2) RCl (1.5
equiv), KI (0.2 equiv) with stirring at 80 °C for 4-12 h; Yields of isolated
products. b RBr was used. c RX (2.0 equiv). d RX (3.0 equiv). e RBr, KI, rt, 12
h. f RBr, KI, 60 °C, 12 h.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
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produce the corresponding (n-C4H9S)2P(O)SR 19−27 under slightly
modified conditions. For benzyl halides, most reactions were
complete within 4 hours; however, for alkyl halides, a longer time
(12 hours) was required. The long-chain 1-chlorooctane gave the
desired products 22 in almost quantitative yield. Alkyl bromide
bearing acetal group could be tolerated at 60 °C to give the desired
product 25 in 83% yield. For other alkyl bromides, the reactions
were conducted at room temperature and gave the corresponding
products with satisfied yields.
1) Formation of (Et)3P
View Article Online
DOI: 10.1039/D0GC02985H
(EtS)3P
standard
conditions
5 min
EtS 2
+
0.25 P4
42
41
 118 ppm
yield: 90%
 519 ppm
(3.0 eq)
43
2) Synthesis of salt
from (EtS)3P
S
standard
conditions
P
SEt
O
+
EtS
(EtS)3P
EtS
2
41
(1.5 eq)
43
42
 75 ppm
yield: >95%
 118 ppm
Encouraged by the findings described above, we continued to
3) 31P NMR spectrum analysis
explore
dialkylphosphorotrithioates which were prepared from various
dialkyldisulfides. In addition to O-potassium S,S-
the
reactivity
of
O-potassium
S,S-
standard
conditions
0.25 P4
(EtS)3P(O)
+
42
+
43
+
44
 63 ppm
C2H5S
2
dibutylphosphorotrithioate, S,S-dimethylphosphorotrithioate, S,S-
diethylphosphorotrithioate, S,S-dipropylphosphorotrithioate, S,S-di-
isopropylphosphorotrithioate, S,S-di-sec-butylphosphorotrithioate,
43
4%
44
5%
6%
0
42
(3.0 eq)
41
5 min
90%
16%
0
15 min
45 min
72%
S,S-dicyclohexylphosphorotrithioate
and
S,S-
98%
dibenzylphosphorotrithioate all could be used as the substrates to
react with benzyl halides, generating the corresponding mixed
phosphorotrithioates (28–34) in 83–95% yields. n-Butyl bromide
could react well with above-mentiond O-potassium S,S-
dialkylphosphorotrithioates to form mixed phosphorotrithioates 35–
40 in good to excellent yield. Diphenyldisulfide was also examined.
42 43
,
44
were all detected by MS
compounds
and
see ESI
4) RS- promoted Michaelis-Arbuzov dealkylation
toluene-DMSO
EtSNa
(EtS)3P
O
+
43
Ar, 80 oC, 4 h
44
 75 ppm
yield: >95%
(2.0 eq)
Unfortunately,
no
desired
O-potassium
S,S-
5) OH- promoted M-A dealkylation
toluene-DMSO
diphenylphosphorotrithioates was detected by 31P NMR.
O
P
SEt
In order to demonstrate the practical application of this method,
the gram-scale experiments were conducted by employing P4 (2.5
mmol, 0.31 g) to deliver 22 and 29 in 94% and 88% yields,
respectively (Scheme 3), indicating this reaction could be scaled up
with a high efficiency.
EtS
KOH
+
44
43
+
O
Ar, 80 oC, 4 h
45
 30 ppm
(2.0 eq)
yield: 31PNMR yield
 75 ppm
total yield: >95%
43:45
= 60:40
O
1) KOH, Tol. DMSO
Ar, 80 oC, x h
2) R2Cl, KI, 80 oC, y h
Scheme 4. Investigation for reaction mechanism.
R1S
R1S
P
SR2
(R1S)2
0.25 P4
+
O
P
expected phosphorotrithioites [P(III), 42] was produced ( = 118
ppm) in 5 minutes and P4 disappeared completely. In the meantime,
there are two obvious peaks that appeared during the synthesis of 42.
The signals at  = 75 and  = 63 ppm belong to salt 43 and
phosphorotrithioate [P(V), 44],40 respectively. Compounds 42, 43
and 44 were all detected by MS (see ESI). As time progressed, the
31P NMR signals of the phosphorotrithioites [P(III), 42] and
phosphorotrithioate [P(V), 44] disappeared gradually and the signal
of salt 43 ( = 75 ppm) increased. The reaction was almost complete
after 45 min according to the 31P NMR spectra (see ESI). During the
reaction course, two new weak peaks at 173 ppm and 180 ppm
emerged; the peaks at 180 ppm disappeared after 30 min. These
signals may belong to penta-coordinate ionic species B and C
(Scheme 5). Although no spectroscopic data for intermediates B and
S
S
C8H17
S
x
P4 (n-C4H9S)2
n-C8H17Cl
KOH
KI
y
22
0.31 g
1.12 g
5.35 g
4 h
4.46 g
0.33 g
12 h
3.49 g, 94% yield
O
S
P
S
Ph
x
P4
(EtS)2
3.67 g
KOH
BnCl KI
1.89 g
y
S
29
0.31 g
1.12 g
4 h
0.33 g
4 h
2.58 g, 88% yield
Scheme 3. Gram-scale preparation of 22 and 29.
To understand the mechanism, further experiments were
conducted (Scheme 4). Carrying out the reaction of (C2H5S)2 (41,
3.0 equivalents of disulfide per P-atom) and P4 in toluene-DMSO
under argon at 80 °C for 5 min generated (C2H5S)3P (42, 118 ppm)
in 90% yield (Scheme 4-1).40 When 1.5 equivalents of (C2H5S)2
C
are available, 1,4,6,9-tetrathia-5-phosphoniaspiro[4.4]nonane
tetrachloroborate has been previously studied by 31P NMR, showing
chemical shifts at 147 ppm,48 similar to our proposed intermediates.
Intermediates B and C were detected by HRMS (Scheme 5, see ESI).
To classify the function of S,S,S-triethy phosphorothioate 44,
carrying out the reaction of sodium ethanethiolate (2.0 equiv) and 44
generated salt 43 in almost quantitative yield (Scheme 4-4). This
result suggests that S,S,S-triethy phosphorothioate 44 was the key
intermediate for the formation of salt 43. To understand whether OH-
promotes Michaelis-Arbuzov dealkylation, KOH was examined. It
reacted
with
(C2H5S)3P
(42),
O-potassium
S,S-
diethylphosphorotrithioate (salt 43, 75 ppm) was obtained in almost
quantitative yield (Scheme 4-2). To further investigate the
mechanism, the formation of salt 43 was monitored by 31P NMR
spectroscopy (see ESI) and the data were shown in Scheme 4-3. The
starting P4 showed signal in the 31P NMR spectrum at  = -519 ppm.
After (C2H5S)2 (41, 3.0 equiv) and KOH were added to the solution
of P4, the reaction was conducted under standard conditions; the
4 | J. Name., 2012, 00, 1-3
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ARTICLE
An oven-dried Schlenk tube with a magnetic stir bar containing
DOI: 10.1039/D0GC02985H
KOH (0.4 mmol, 22.4 mg) was evacuated and purged with argon
was found that the reaction gave both the normal dealkylated salt 43
and the saponification product 45 as a 60:40 mixture when KOH was
used instead of EtSNa (Scheme 4-5). This result suggests that RS-
played a key role in Michaelis-Arbuzov dealkylation.
View Article Online
three times. White phosphorus-toluene solution (6.2 mg total P4, 0.5
mL, 0.1 mol/L) was added. Then (n-C4H9S)2 (107.0 mg, 0.6 mmol),
and DMSO (0.5 mL) were sequentially added to the system at room
temperature. The reaction mixture was stirred for 4 hours at 80 °C.
After completion, KI (0.02 mmol, 6.6 mg) and benzyl chloride (0.3
mmol, 37.8 mg) was added under air, and the mixture was stirred at
80 °C for another 4 hours. Saturated brine (3 mL) was added into the
above reaction mixture. The mixture was extracted by EtOAc (3×2.0
mL). The combined organic layer concentrated by rotary
evaporation. The crude reaction mixture was purified by flash
chromatography using n-hexane−AcOEt [from 50:1 to 10:1 (v/v)] as
the eluent to give the product 4 (66 mg, 95%).
(RS)2
SR
SR
SR
OH
OH
SR
SR
RS
RS
P
SR
RS
(RS)2
P
P
+
KOH
RS
RS
SR
P
RS
or
C
A
B
P
P
P
OH
O
SR
R'
OH
S
O
RS
RS
RS
RS
P
P
P
SR
SR
P
RS
S
SK
RS
OK
RS
RS
R2S
RS
(R = CH2R')
F
E
D
G
Gram-scale synthesis of (C2H5S)2P(O)SBn (29) from (C2H5S)2,
white phosphorus (P4) and benzylchloride
Scheme 5. Tentative mechanistic pathway
.
A 100 mL-round bottomed Schlenk flask with a magnetic stir bar
containing KOH (1.12 g, 20.0 mmol) was evacuated and purged with
argon three times. White phosphorus-toluene solution (0.31 g total
P4, 25.0 mL, 0.1 mol/L) was added. Then (C2H5S)2 (3.67 g, 30.0
mmol), and DMSO (25.0 mL) were sequentially added to the system
at room temperature. The reaction mixture was stirred for 4 hours at
80 °C. After completion, KI (0.33 g, 2.0 mmol) and benzylchloride
(1.89 g, 15.0 mmol) was added under air, and the mixture was stirred
at 80 °C for another 4 hours. Saturated brine (25.0 mL) was added
into the above reaction mixture. The mixture was extracted by
EtOAc (4×20.0 mL). The combined organic layer was dried over
anhydrous MgSO4, filtered, and concentrated by rotary evaporation.
The crude reaction mixture was purified by flash chromatography
using n-hexane−AcOEt [from 50:1 to 10:1 (v/v)] as the eluent to
give the product 29 (2.58 g, 88%).
Based on the above experiments and previous reports, a possible
reaction mechanism is depicted in Scheme 5. Initially, the coupling
of disulfide and P4 affords phosphorotrithioites [P(III), A] in the
presence of KOH under argon.40 Reaction of phosphorotrithioites
(P(III), A) with disulfide results in penta-coordinate ionic species
B.48,49 Ionic species B reacts with KOH to give intermediates C and
D via an anion exchange. Phosphorotrithioate [P(V), E] is produced
by elimination reaction of nonpolar penta-coordinate intermediate D.
The attack of RSK to phosphorotrithioate E takes place and C−S
bond breaks, the Michaelis-Arbuzov-like dealkylation, to form salt
F/G along with the release of R2S. A final alkylation of salt F/G
gives mixed phosphorotrithioate.
Conclusions
In summary, we have successfully developed the first general and
high yielding synthesis of (R1S)2P(O)SR2 involving P4, disulfides
and alkyl halides. The use of KOH as a base, DMSO-toluene as a
solvent, makes this transformation practical and green. The
operationally simple reaction shows a broad scope of substrates and
a good functional group tolerance. This method opens the shortest
and environmentally benign way to these mixed phosphorotrithioates
of practical importance. The reaction is characterized by a complete
conversion of white phosphorus. Moreover, this method can be
easily adapted to large-scale preparation. Our mechanistic data
suggest that the nucleophilic attack of RSK on S,S,S-trialkyl
phosphorotrithioates and subsequent C−S bond cleavage, the
Michaelis-Arbuzov-like dealkylation, are the key steps in the
formation of (R1S)2P(S)OK.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This project was supported by the NSFC (21772163, 21778042) and
NFFTBS (J1310024).
Notes and references
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